Project Summary Psychiatric Genomics Consortium for PTSD Posttraumatic stress disorder (PTSD) occurs only in vulnerable individuals after exposure to severe traumatic events. This risk is due, in part, to 40-50% heritability of differential vulnerability. Due to increasing collaborations across the field of PTSD genomics and the advent of new analytical tools, it is a very exciting time for PTSD genetic risk discovery. The purpose of this application is to facilitate meta-analyses of genome- wide association study (GWAS) data for symptoms and diagnosis of PTSD. We propose to conduct large-scale meta-analyses through the PTSD group of the Psychiatric Genomics Consortium (PGC). The PGC was created in 2007 to conduct field-wide mega-analyses of individual data for 5 major psychiatric disorders. With its current 11 working groups, it is the largest consortium (>800 scientists from 40 countries) in the history of psychiatry. The PGC has produced major findings with regard to the genetic architecture of psychiatric disorders. Meta-analyses of GWAS have produced over 100 loci at the genome- wide significance threshold, at sample sizes ranging from 36,000 cases for schizophrenia to 246K cases for depression. The polygenic architecture inferred from family studies was confirmed with molecular evidence. Corroborating findings from twin studies, shared genetic contributions among psychiatric disorders has been found. The PGC-PTSD group was launched in 2013 and has been enormously successful. Currently our multi- ethnic data collection includes genotypes from 60 studies with a total N of over 200K combined cases and trauma-exposed controls. We recently identified 6 genome-wide significant loci and generated a polygenic risk score to identify individuals at highest risk for PTSD after trauma exposure. We hypothesize that with an increased sample size and deeper phenotype characterization, the PGC- PTSD will accelerate our current understanding of the genetic architecture of PTSD. Our progress thus far demonstrates feasibility and initial successes of the proposed work. Aim 1 will increase sample size (with commitments for 50K additional cases and 300K controls from banked samples) to reach the PGC goal of 100K cases for psychiatric disorders, create psychometrically optimized PTSD subphenotypes, conduct GWAS meta-analyses to detect novel common variants, and identify copy-number variants (CNVs) hypothesized to contribute to PTSD heritability through rare and low-frequency CNVs. This aim will be supplemented by the contribution of diverse ancestry groups to ensure that advances in our genetic understanding of PTSD extend across ancestral backgrounds in Aim 2. Aim 3 is centered around the characterization of functional consequences of identified variants. Lastly, we will use polygenic risk scores (PRS) to provide insights into relationships to other traits and advance causal inference in Aim 4. Identifying the genetic pathways underlying PTSD will lead to improved neurobiological understanding, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome.